Cardiac GR Mediates the Diurnal Rhythm in Ventricular Arrhythmia Susceptibility.

BACKGROUND: Ventricular arrhythmias (VAs) demonstrate a prominent day-night rhythm, commonly presenting in the morning. Transcriptional rhythms in cardiac ion channels accompany this phenomenon, but their role in the morning vulnerability to VAs and the underlying mechanisms are not understood. We investigated the recruitment of transcription factors that underpins transcriptional rhythms in ion channels and assessed whether this mechanism was pertinent to the heart's intrinsic diurnal susceptibility to VA. METHODS AND RESULTS: Assay for transposase-accessible chromatin with sequencing performed in mouse ventricular myocyte nuclei at the beginning of the animals' inactive (ZT0) and active (ZT12) periods revealed differentially accessible chromatin sites annotating to rhythmically transcribed ion channels and distinct transcription factor binding motifs in these regions. Notably, motif enrichment for the glucocorticoid receptor (GR; transcriptional effector of corticosteroid signaling) in open chromatin profiles at ZT12 was observed, in line with the well-recognized ZT12 peak in circulating corticosteroids. Molecular, electrophysiological, and in silico biophysically-detailed modeling approaches demonstrated GR-mediated transcriptional control of ion channels (including Scn5a underlying the cardiac Na+ current, Kcnh2 underlying the rapid delayed rectifier K+ current, and Gja1 responsible for electrical coupling) and their contribution to the day-night rhythm in the vulnerability to VA. Strikingly, both pharmacological block of GR and cardiomyocyte-specific genetic knockout of GR blunted or abolished ion channel expression rhythms and abolished the ZT12 susceptibility to pacing-induced VA in isolated hearts. CONCLUSIONS: Our study registers a day-night rhythm in chromatin accessibility that accompanies diurnal cycles in ventricular myocytes. Our approaches directly implicate the cardiac GR in the myocyte excitability rhythm and mechanistically link the ZT12 surge in glucocorticoids to intrinsic VA propensity at this time.

KRAS status predicted by pretreatment MRI radiomics was associated with lung metastasis in locally advanced rectal cancer patients.

BACKGROUND: Mutated KRAS may indicate an invasive nature and predict prognosis in locally advanced rectal cancer (LARC). We aimed to establish a radiomic model using pretreatment T2W MRIs to predict KRAS status and explore the association between the KRAS status or model predictions and lung metastasis. METHODS: In this retrospective multicentre study, LARC patients from two institutions between January 2012 and January 2019 were randomly divided into training and testing cohorts. Least absolute shrinkage and selection operator (LASSO) regression and the support vector machine (SVM) classifier were utilized to select significant radiomic features and establish a prediction model, which was validated by radiomic score distribution and decision curve analysis. The association between the model stratification and lung metastasis was investigated by Cox regression and Kaplan‒Meier survival analysis; the results were compared by the log-rank test. RESULTS: Overall, 103 patients were enrolled (73 and 30 in the training and testing cohorts, respectively). The median follow-up was 38.1 months (interquartile range: 26.9, 49.4). The radiomic model had an area under the curve (AUC) of 0.983 in the training cohort and 0.814 in the testing cohort. Using a cut-off of 0.679 defined by the receiver operating characteristic (ROC) curve, patients with a high radiomic score (RS) had a higher risk for lung metastasis (HR 3.565, 95% CI 1.337, 9.505, p = 0.011), showing similar predictive performances for the mutant and wild-type KRAS groups (HR 3.225, 95% CI 1.249, 8.323, p = 0.016, IDI: 1.08%, p = 0.687; NRI 2.23%, p = 0.766). CONCLUSIONS: We established and validated a radiomic model for predicting KRAS status in LARC. Patients with high RS experienced more lung metastases. The model could noninvasively detect KRAS status and may help individualize clinical decision-making.

Disease activity in patients with synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome: the utility of the SPARCC MRI scoring system for assessment of axial spine involvement.

OBJECTIVES: The aim of this study is to investigate the relationship between spinal MRI findings with disease activity and other clinical and serological parameters, and to determine the importance of MRI scoring system in evaluating disease activity of SAPHO syndrome. METHODS: Thirty patients with SAPHO syndrome underwent clinical, laboratory and MRI evaluation at baseline, 3 months, 6 months and 1 year. Magnetic resonance images were analysed using modified Spondyloarthritis Research Consortium of Canada (SPARCC) scoring system. Correlations between MRI score and clinical and laboratory parameters were analysed using Spearman's rank correlation test. RESULTS: Persistent improvement was observed after 12 months in terms of total modified SPARCC scores (37(12,59) vs. 23(5,45) at baseline and 12 months, p<0.05). Total modified SPARCC scores showed Spearman correlations with hypersensitive C-reaction protein (hs-CRP), ankylosing spondylitis disease activity score (ASDAS) and bath ankylosing spondylitis metroloty index (BASMI) at baseline, 3 months, 6 months and 12 months (p varied from <0.001 to <0.05, and r varied from 0.418 to 0.601). Modified SPARCC scores of spine joint, as the largest contribution to the total scores with the mean score of 12(5,30) after 12 months vs. 26 (12,40) at baseline. CONCLUSIONS: The modified SPARCC score proposed in this study exhibits promising potential in the evaluation of extensive radiographic damage in SAPHO and the reflection the disease activity. Our study suggests that MRI could be used together with other parameters of disease activity in the assessment of symptomatic SAPHO patients with spine involvement.

Serum IgG4 elevation in SAPHO syndrome: does it unmask a disease activity marker?

OBJECTIVES: SAPHO syndrome is a rare inflammatory disorder with multiple phenotypes, including synovitis, acne, pustulosis, hyperostosis, and osteitis. IgG4 is a subclass of immunoglobulin G, and the elevation of IgG4 has been found in different autoimmune diseases. In the present study, we explored the clinical significance of serum IgG4 levels in patients with SAPHO syndrome. METHODS: Fifty-two patients who met the classification criteria of SAPHO syndrome were included in this study. Clinical data and disease activity markers were collected including erythrocyte sedimentation rate (ESR), high sensitivity C-reactive protein (hsCRP), pain visual analogue scale (VAS), Bath Ankylosing Spondylitis Metrology Index (BASMI), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI) and Ankylosing Spondylitis Disease Activity Score (ASDAS). Serum immunoglobin (IgA, IgM, and IgG) and IgG subclass (IgG1, IgG2, IgG3, and IgG4) levels were determined using the immunonephelometric assay. RESULTS: Raised serum IgG4 levels (>1400 mg/dL) were detected in 23% (12/52) of patients. Patients with elevated sIgG4 levels had significantly higher pain VAS (5.42±2.76 vs. 3.08±1.78, p=0.02), BASMI (1.80±1.64 vs. 0.38±0.94, p=0.03) and ASDAS (3.20±0.65 vs. 1.74±0.58, p<0.001) levels compared with patients with normal sIgG4 levels. This difference was also observed for ESR (38.2 vs. 22.2 mm/h, p=0.01) and serum CRP (21.0 vs. 2.2 mg/L, p=0.04) levels, which also positively correlated with sIgG4 levels. We also included 4 patients whose IgG4 levels decreased and correlated with the decrease in hsCRP and ESR levels after treatment. CONCLUSIONS: Elevated sIgG4 levels are common in patients with SAPHO syndrome and are associated with high disease activity. Further investigations are needed for this phenomenon.

The ypT may better predict the efficacy of neoadjuvant chemoradiotherapy than tumor regression grade in locally advanced rectal cancer patients diagnosed ypT1-4N0.

PURPOSE: This study aimed to assess the impact of ypT stage and tumor regression grade (TRG) on the long-term prognosis of patients with locally advanced rectal cancer (LARC) stage ypT1-4N0 after neoadjuvant chemoradiotherapy (NCRT). METHODS: We retrospectively analyzed 585 patients with histologically diagnosed middle-low LARC (cT3-4 or cN + by pelvic MRI) from 2014 to 2019. All patients underwent NCRT, followed by total mesorectal excision. Disease-free survival (DFS) rates were compared among patients with different ypT stages and TRGs by Kaplan-Meier survival analysis. The chi-square test was used to analyze the relationship between clinicopathological or therapeutic factors and ypT stage. RESULTS: The median follow-up was 35.8 months (range 2.8-71.8 months). The 3-year DFS was 79.5%. A better 3-year DFS was achieved in patients with a pathologic complete response (94.0% vs. 74.3%, p < 0.001) and those in the ypT0-2 (86.5% vs. 66.6%, p < 0.001), ypN0 (85.0% vs. 60.2%, p < 0.001), and TRG0 + 1 (83.1% vs. 73.0%, p = 0.004) subgroups. A total of 309 patients (52.8%) achieved stage ypT1-4N0 after surgery. Among these patients, the ypT1-2N0 subgroup achieved a significantly higher 3-year DFS than the ypT3-4N0 subgroup (85.4% vs. 72.8%, p = 0.018); in contrast, the 3-year DFS did not significantly differ between the TRG1 and TRG2 + 3 subgroups (79.9% vs. 81.1%, p = 0.833). In the ypT1-2N0 or ypT3-4N0 subgroup, different TRG had no significant effect on failure patterns. CONCLUSIONS: For LARC patients with a ypT1-4N0 status after NCRT, ypT stage may be a more effective predictor of long-term prognosis than TRG.

MRI-based radiomics to predict neoadjuvant chemoradiotherapy outcomes in locally advanced rectal cancer: A multicenter study.

Background and purpose: Predicting tumour response would be useful for selecting patients with locally advanced rectal cancer (LARC) for organ preservation strategies. We aimed to develop and validate a prediction model for T downstaging (ypT0-2) in LARC patients after neoadjuvant chemoradiotherapy and to identify those who may benefit from consolidation chemotherapy. Materials and methods: cT3-4 LARC patients at three tertiary medical centers from January 2012 to January 2019 were retrospectively included, while a prospective cohort was recruited from June 2021 to March 2022. Eight filter (principal component analysis, least absolute shrinkage and selection operator, partial least-squares discriminant analysis, random forest)-classifier (support vector machine, logistic regression) models were established to select radiomic features. A nomogram combining radiomics and significant clinical features was developed and validated by calibration curve and decision curve analysis. Interaction test was conducted to investigate the consolidation chemotherapy benefits. Results: A total of 634 patients were included (426 in training cohort, 174 in testing cohort and 34 in prospective cohort). A radiomic prediction model using partial least-squares discriminant analysis and a support vector machine showed the best performance (AUC: 0.832 [training]; 0.763 [testing]). A nomogram combining radiomics and clinical features showed significantly better prognostic performance (AUC: 0.842 [training]; 0.809 [testing]) than the radiomic model. The model was also tested in the prospective cohort with AUC 0.727. High-probability group (score > 81.82) may have potential benefits from ≥ 4 cycles consolidation chemotherapy (OR: 4.173, 95 % CI: 0.953-18.276, p = 0.058, pinteraction = 0.021). Conclusion: We identified and validated a model based on multicenter pre-treatment radiomics to predict ypT0-2 in cT3-4 LARC patients, which may facilitate individualised treatment decision-making for organ-preservation strategies and consolidation chemotherapy.

Tonsillitis as a possible predisposition to synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome.

AIM: To present the prevalence of tonsillitis in synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) patients, to compare the clinical characteristics and disease activities between SAPHO patients with and without tonsillitis and to preliminarily explore the efficacy of tonsillectomy in SAPHO syndrome. METHOD: A total of 58 SAPHO patients were included. Clinical data were collected, including demographic characteristics and acute phase reactants (erythrocyte sedimentation rate, high-sensitivity C-reactive protein). The visual analog scale (VAS), Palmoplantar Pustule Psoriasis Area Severity Index (PPPASI) and Nail Psoriasis Severity Index (NAPSI) were used to measure the severity of bone pain, skin lesions and nail lesions, respectively. Patients were referred to the otolaryngology department for tonsil examinations, including tonsil hypertrophy (grade ≥ 2), chronic congestion, inflammatory secretion and tonsil stones. The patients who underwent tonsillectomy were followed up after the surgery. RESULTS: A total of 67.2% of patients had tonsillitis. Patients with tonsillitis had markedly higher PPPASI (1.2 [0, 7.4] vs. 7.6 [1.75, 15.5], P = .018) and NAPSI (0 [0, 21] vs. 8 [3, 28], P = .032) scores. After tonsillectomy, the patients experienced significantly improved bone pain (VAS, 5 [4, 7] vs. 3 [1, 4], P = .034) and skin lesions (PPPASI, 16.2 [7.05, 18.35] vs 1.8 [0.7, 3.7], P = .028). CONCLUSION: Approximately 2/3 of SAPHO patients had tonsillitis. Patients with tonsillitis had more severe skin and nail lesions. Tonsillectomy might be associated with improved bone and skin symptoms in SAPHO patients. Future prospective controlled studies are warranted.

Fibromyalgia in patients with synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome: prevalence and screening.

OBJECTIVE: To explore the prevalence, clinical characteristics, and screening strategy for fibromyalgia (FM) in patients with synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome. METHODS: A total of 313 patients from a cohort of 354 SAPHO patients volunteered to participate in this study. Demographic, clinical and laboratory data were collected at baseline. Acute-phase reactants during the last 3 months were obtained. Patient-reported outcomes (PROs) and FM evaluation were recorded by questionnaires. RESULTS: A total of 57 (18.2%) patients met the 2016 research criteria for FM. Compared to those without FM, these patients had significantly higher visual analog scale (VAS), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Bath Ankylosing Spondylitis Functional Index (BASFI) scores (all p < 0.001). However, no differences in the erythrocyte sedimentation rate (ESR) or hypersensitive C-reactive protein (hs-CRP) levels were identified between the two groups. Patients with FM were also markedly older [odds ratio (OR) 1.072, p = 0.032] and had higher Fibromyalgia Rapid Screening Tool (FiRST) scores (OR 1.607, p = 0.016). The FiRST score showed a sensitivity of 50.9% and a specificity of 89.8%, and with a cutoff of 3, the FiRST score presented a high sensitivity of 84.2%. CONCLUSION: The prevalence of FM among SAPHO patients was similar to that among patients with other rheumatic diseases. Concomitant FM in SAPHO syndrome was associated with older age and worse PROs. Different cutoff values for FiRST screening should be used in patients with SAPHO syndrome. Key Points • The prevalence of FM among SAPHO patients was similar to that among patients with other rheumatic diseases. • Concomitant FM in SAPHO syndrome was associated with older age, widespread pain, and worse PROs. • Different cutoff values for FiRST screening should be used in patients with SAPHO syndrome.

Chinese SLE Treatment and Research Group Registry (CSTAR) XIII: prevalence and risk factors for chronic scarring alopecia in patients with systemic lupus erythematosus.

BACKGROUND: Scarring alopecia in systemic lupus erythematosus (SLE) patients caused reduced life quality and prolonged disease course. This case-control study aims to survey the prevalence of scarring alopecia during the disease course of SLE and evaluate the risk factors for scarring alopecia in Chinese SLE patients. METHODS: SLE patients in Chinese SLE treatment and Research group (CSTAR) were recruited. Scarring alopecia was defined according to SLICC/ACR-DI which was collected during follow-up visits or via self-reported questionnaires. We collected demographic characteristics, common comorbidities, autoantibody profiles, disease activity status, major organ involvements, and treatment strategies of these patients at registry. Univariate and multivariate logistic regression analyses were used to investigate the risk factors for scarring alopecia. RESULTS: We recruited 4792 SLE patients, and 374 (7.80%) patients had scarring alopecia. Mucocutaneous lesions (OR 2.062, p < 0.001), high SLICC/ACR-DI (OR 1.409, p < 0.001), and positive anti-Sm (OR 1.374, p = 0.029) were risk factors for scarring alopecia, while renal (OR 0.714, p = 0.028) and cardio-respiratory involvements (OR 0.347, p = 0.044), and immunosuppressant treatment (OR 0.675, p < 0.001) were significantly negative associated with it. CONCLUSIONS: The prevalence of scarring alopecia in SLE patients is 7.80%. Active treatment strategies should be adopted to prevent scarring alopecia occurring.

Factors Associated With Renal Involvement in Primary Sjögren's Syndrome: A Meta-Analysis.

Background: Renal impairment is a critical complication in primary Sjögren's syndrome (pSS), resulting in chronic renal disease and even death. This meta-analysis was designed to find out the relevant factors of renal involvement in pSS. Methods: PubMed, EMBASE, Cochrane Library, Scopus, and Web of Science were systemically searched until August 30, 2019. Studies were selected according to inclusion criteria, and data was extracted by two researchers independently. The Newcastle-Ottawa Scale was applied for quality assessment. Random- and fixed-effects models were used in this meta-analysis based on the result of the heterogeneity test. Meanwhile, a sensitivity analysis was conducted to investigate the cause of heterogeneity. Publication bias was shown in the funnel plot and evaluated further by Begg's and Egger's tests. Results: Of the 9,989 articles identified, five articles enrolling 1,867 pSS patients were included in the final analysis, 533 with and 1,334 without renal involvement. There was no statistical significance in age and gender between these two groups. According to the meta-analysis, anti-SSB antibody, and arthralgia showed a significant association with renal involvement in pSS, the overall odds ratio (OR) values of which were 1.51 (95% CI, 1.16-1.95) and 0.59 (95% CI, 0.46-0.74), respectively. On the other hand, the overall OR values of anti-SSA antibody, rheumatoid factor, dry eyes, and labial salivary gland biopsy were just 0.90 (95% CI, 0.49-1.64), 1.05 (95% CI, 0.59-1.86), 0.60 (95% CI, 0.34-1.06), and 1.38 (95% CI, 0.98-1.95), respectively. Conclusion: The presence of anti-SSB antibody is positively associated with renal involvement in pSS, while arthralgia is inversely associated. Large-scale prospective cohort studies are needed in the future to identify further risk factors.

Chinese registry of rheumatoid arthritis (CREDIT): III. The transition of disease activity during follow-ups and predictors of achieving treatment target.

AIM: The Chinese Registry of Rheumatoid Arthritis (CREDIT) is the first nationwide multi-center prospective rheumatoid arthritis (RA) registration cohort in China. This study aimed at presenting disease activities transition during follow-ups and identifying predictors to treatment response. METHOD: Patients who had baseline, 3- and 6-month follow-up data from November 2016 to April 2018 were recruited. Then, we selected patients who did not reach remission (REM)/low disease activity (LDA) at baseline to investigate the predictors for treatment response. RESULTS: There were 979 patients included (83.00% female, mean age 51.8 and median duration 3.84 years). REM/LDA rate at baseline, 3-, and 6-month follow-up were 34.02%, 59.35% and 68.23%. Additionally, early RA has more chance to achieve targets than established RA (6 months: 59.79% vs 48.13%, P = .002). High baseline Disease Activity Score of 28 joints (DAS28) (early RA: odds ratio [OR] 1.319, P = .019; established RA: OR 1.337, P < .001), biologic disease-modifying anti-rheumatic drugs (bDMARD)/targeted synthetic DMARD combined conventional DMARD therapy (early RA: OR 9.023, P = .046) and prednisolone usage (early RA: OR 2.526, P < .001) are positively associated with Clinical Disease Assessment Index (CDAI) decreasing at 3 months. Low baseline DAS28 (REM/LDA: early RA: OR 0.650, P < .001; established RA: OR 0.612, P < .001. REM: early RA: OR 0.743, P = .021; established RA: OR 0.674, P < .001), young age (REM: early RA: OR 0.977, P = .048) and decrease of CDAI at 3 months (REM/LDA: early RA: OR 7.185, P < .001; established RA: OR 8.752, P < .001. REM: early RA: OR 5.602, P < .001; established RA: OR 4.955, P < .001) predict REM/LDA at 6 months. CONCLUSION: Disease activity decreased during follow-ups. Disease duration, baseline disease activity, age, treatment strategies, and CDAI decreasing were associated with treatment response.

The ypT may better predict the efficacy of neoadjuvant chemoradiotherapy than tumor regression grade in locally advanced rectal cancer patients diagnosed ypT1-4N0 / El ypT puede predecir mejor la eficacia de la quimiorradioterapia neoadyuvante que el grado de regresión tumoral en pacientes con cáncer de recto localmente avanzado diagnosticados ypT1-4N0

Purpose: This study aimed to assess the impact of ypT stage and tumor regression grade (TRG) on the long-term prognosis of patients with locally advanced rectal cancer (LARC) stage ypT1-4N0 after neoadjuvant chemoradiotherapy (NCRT). Methods: We retrospectively analyzed 585 patients with histologically diagnosed middle-low LARC (cT3-4 or cN + by pelvic MRI) from 2014 to 2019. All patients underwent NCRT, followed by total mesorectal excision. Disease-free survival (DFS) rates were compared among patients with different ypT stages and TRGs by Kaplan–Meier survival analysis. The chi-square test was used to analyze the relationship between clinicopathological or therapeutic factors and ypT stage. Results: The median follow‐up was 35.8 months (range 2.8–71.8 months). The 3-year DFS was 79.5%. A better 3-year DFS was achieved in patients with a pathologic complete response (94.0% vs. 74.3%, p < 0.001) and those in the ypT0-2 (86.5% vs. 66.6%, p < 0.001), ypN0 (85.0% vs. 60.2%, p < 0.001), and TRG0 + 1 (83.1% vs. 73.0%, p = 0.004) subgroups. A total of 309 patients (52.8%) achieved stage ypT1-4N0 after surgery. Among these patients, the ypT1-2N0 subgroup achieved a significantly higher 3-year DFS than the ypT3-4N0 subgroup (85.4% vs. 72.8%, p = 0.018); in contrast, the 3-year DFS did not significantly differ between the TRG1 and TRG2 + 3 subgroups (79.9% vs. 81.1%, p = 0.833). In the ypT1-2N0 or ypT3-4N0 subgroup, different TRG had no significant effect on failure patterns. Conclusions: For LARC patients with a ypT1-4N0 status after NCRT, ypT stage may be a more effective predictor of long-term prognosis than TRG.(AU)